Obese women clearly are at increased risk for developing endometrial cancer. Numerous epidemiologic studies have demonstrated that obesity is strongly associated with an increased risk of endometrial cancer. While an average woman has a 3% lifetime risk of endometrial cancer, obese women have a 9-10% lifetime risk of endometrial cancer. In a review of diet and cancer by the American Institute for Cancer Research and World Cancer Research Fund (WCRF), authors stated that the evidence relating body mass index and cancer is strongest for endometrial cancer. While excessive production of extragonadal estrogens (estrone) in the adipose tissue of obese women is presumed to be the major contributor to the risk of endometrial cancer, increased serum estrogen levels alone are unlikely to fully account for this effect. Studies by our group and others suggest that insulin resistance associated with obesity contributes to the increased risk of endometrial cancer. In addition, data from our previous funding period suggest that other mechanisms are involved in activating pro-proliferative signaling pathways in the obese endometrium. For the current proposal, our central hypothesis is that metformin can decrease endometrial hyperproliferation and can act as a chemopreventive agent in insulin-resistant obese women. Our three specific aims are 1) to test the hypothesis that metformin can reverse the estrogen-dependent hyperproliferation in the endometrium in an animal model of obesity- induced insulin-resistance, 2) to study novel mechanisms related to the use of metformin for the prevention of endometrial cancer. More specifically, we will examine the hypothesis that adipokines expressed in adipose tissue regulate endometrial proliferation via adipokine receptors, and metformin treatment can prevent this proliferation, and 3) to assess the ability of metformin to modulate surrogate endometrial biomarkers in a cohort of obese, insulin resistant women. It is the goal of this Project to develop novel strategies for the chemoprevention of endometrial cancer in obese, insulin resistant women, a high risk cohort.